Seeinstructions): The phospholipid sphingomyelin (SM) is thought to be a significant regulator of pathogenesis of atherosclerosis; however, in contrast to our understanding of the role of cholesterol in vascular disease, our understanding in this area is limited. Metabolism of SM releases bioactive mediators such as sphingosine 1- phosphate (S1P). Studies supported by this PPG have shown that S1P interaction with the vascular system is cell context- and receptor-specific. Our recent studies show that mice that lack the S1p2r gene exhibit marked suppression of atherosclerosis in the Apoe-/- background. Microarray profiling experiments revealed that S1P2R signaling is essential for the expression of caspase 11, an inflammasome-specific protease involved in the secretion of the inflammatory cytokines IL-1f3 and IL-18. These data allow us to propose that S1P2R signaling within the myeloid compartment is critical for the progression of the atherosclerotic plaque by the regulation of inflammasome function. Thus the central hypothesis is : Enhanced production of S1P in the atherosclerotic plaque as well as autocrine signaling activates myeloid S1PRs and regulates macrophage phenotype and fate. Specifically, macrophage S1P2R sustains pathologic vascular inflammation by regulation of expression of inflammasome-specific caspase-11. The first aim will focus on how S1P2R signaling in the macrophage regulates inflammasome function and cytokine release. The second aim will test if macrophage S1P2R/ caspase-11 pathway is necessary and/or sufficient in atherosclerotic plaque development of the Apoe null mouse. Thirdly, we will explore the hypothesis that the anti-inflammatory S1P1R antagonizes the proinflammatory receptors -S1P2R and S1P3R to fine-tune the macrophage responses during atherosclerosis. These data are anticipated to enhance our understanding of the role of sphingolipid signaling in atherosclerosis. Furthermore, knowledge gained from this study maybe useful as a new approach to control atherosclerosis using S1P receptor-based pharmacological tools. RELEVANCE (See instructions): Atherosclerosis, or hardening of arteries, causes heart attacks. We have found that a specific lipid mediator called sphingosine 1-phosphate (S1P) activates its receptor on macrophages in the atherosclerotic plaque and regulates inflammation. We propose to fully define this novel mechanism in mouse models of atherosclerosis. This work could lead to the discovery of new agents to block heart disease.